MAPK signaling and angiopoietin-2 contribute to endothelial permeability in capillary malformations.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41259140.
- Also identified by DOI 10.1073/pnas.2509528122 and PMC identifier 12664009.
- Licence recorded as CC BY-NC-ND.
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Abstract
Nonsyndromic capillary malformations (CM) are seen predominantly in skin. In Sturge-Weber Syndrome (SWS), CMs occur in the skin, leptomeninges of the brain, and choroid of the eye. >90% of CM are caused by a somatic mutation-<i>GNAQ</i> p.R183Q, the gene encoding the G-protein subunit Gα<sub>q</sub>. Longitudinal MRI of the brain in one SWS patient suggests developing vascular permeability. We modeled this in a transendothelial electrical resistance assay and found endothelial cells with <i>GNAQ</i> p.R183Q (EC-R183Q) exhibited increased permeability compared to EC wild-type. Increased vascular permeability was confirmed in a <i>Gnaq</i> p.R183Q mouse model. Knockdown of elevated angiopoietin-2 (ANGPT2) in EC-R183Q partially restored the EC barrier, as did a MEK1,2 inhibitor, implicating MAPK/ERK signaling. The combination of ANGPT2 knockdown and trametinib further restored the EC barrier in an additive manner. indicating the two operate in separate pathways. In summary, we found that EC-R183Q exhibits increased permeability, reflecting the compromised endothelial barrier in CMs.
Medical subject headings
- Angiopoietin-2
- Capillary Permeability
- MAP Kinase Signaling System
- Capillaries
- Sturge-Weber Syndrome
- Vascular Malformations